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Home , Dofetilide

5/13/2021

Disclosure Statement

Nicolas Tran, Pharm.D. (speaker) has disclosed that he has no relevant financial disclosures. No one else in a position to control content has any financial relationships to disclose.

Safety of Immediate Dofetilide Initiation Post Whitney Gibson, Pharm.D., BCCCP (advisor) has disclosed that Therapy she has no relevant financial disclosures. No one else in a position to control content has any financial relationships to disclose. Nicolas Tran, Pharm.D. Czarina Bock, Pharm.D., BCPS, BCCCP (advisor) has disclosed PGY‐1 Pharmacy Resident that she has no relevant financial disclosures. No one else in a Tampa General Hospital position to control content has any financial relationships to [email protected] disclose.

2 Nicolas Tran, Pharm.D. 12

Presentation Objective Background

Rate Rhythm At the completion of this activity, the participant Control Control will be able to: • Describe the safety of rapidly transitioning from amiodarone to dofetilide in patients with atrial fibrillation without regard to the presence of an implantable cardioverter‐defibrillator.

Thompson. JAMA. 2015;313(10):1070 3 4 Nicolas Tran, Pharm.D. Nicolas Tran, Pharm.D. 34

Background Dofetilide Clinical Trials

Amiodarone (Cordarone®) Trial Intervention Restoration of NSR Incidence of TdP Notes

Dofetilide 500 mcg BID 29.5% (dofetilide) vs Mechanism of Action Class III Antiarrhythmic Drug Abstract only; no explicit EMERALD or 80 mg BID vs 5.9% (sotalol) 4/397 (1.0%) exclusion criteria listed T½: 40‐55 days (range 26‐107 days) placebo [3 day]

Adverse Events Dofetilide 500 mcg BID 29.9% vs 1.2% Exclusion criteria: amiodarone SAFIRE‐D x 3 days 2/241 (0.8%) [3 day] blood levels >0.3 mg/mL vs. placebo

Dofetilide 250‐1000 Exclusion criteria: amiodarone DIAMOND 22% vs 3% MI – 6/749 (0.8%) mcg/day treatment within the last 3 (CHF & MI) [1 month] CHF – 25/762 (3.3%) vs placebo months Dofetilide (Tikosyn®) Abbreviations: BID: twice daily; NSR: normal sinus rhythm; TdP: Mechanism of Action Class III Antiarrhythmic Drug A washout period of 3 months is recommended when switching FDA Indications Rhythm control –Atrial Fibrillation and from amiodarone to dofetilide to avoid serious cardiac Clinical Trials SAFIRE‐D, EMERALD, DIAMOND based on expert opinion and pharmacokinetics of amiodarone

Colunga Biancatelli R, et al. Journal of Geriatric Cardiology. 2019;16:552‐566 Cordarone (amiodarone) [package insert]. Philadelphia, PA: Sanofi; 2004 Torp‐Pedersen C, et al. NEJM. 1999;341(12):857‐865 Singh S, et al. Circulation. 2000;102:2385‐2390 T½: half‐life 5 6 Tikosyn (dofetlide) [package insert]. New York, NY: ; August 2019 Kober L, et al. Lancet. 2000;356:2052‐2058 Greenbaum R, et al. Circulation. 1998;98(Suppl 17):1633 Nicolas Tran, Pharm.D. Nicolas Tran, Pharm.D. 56

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Current Literature Current Literature

Primary Outcomes Safety of rapid switching from amiodarone to dofetilide in atrial fibrillation •Drug discontinuation during initiation phase – patients with an implantable cardioverter‐defibrillator (ICD) 6.1% (11/179) Clinical question Is it safe to rapidly switch from amiodarone to dofetilide •Reasons for discontinuation after seven days of discontinuing amiodarone? • Persistent QTc prolongation –5% (9/179) Authors’ Conclusions Trial design Retrospective chart review •Torsades de Pointes (TdP) –1.1% (2/179) Patients Diagnosed atrial fibrillation with an ICD (n=179) It is safe to initiate Secondary Outcomes dofetilide after 7 days of Primary outcome Safety of using dofetilide after seven days of discontinuing • 88% of patients were discharged in NSR discontinuing amiodarone amiodarone in patients with an ICD •Patients remained in NSR Secondary outcomes Efficacy of converting to normal sinus rhythm and •At 3 months – 78% of (140/179) maintenance of normal sinus rhythm •At 6 months – 70% of (125/179) •At 12 months – 67% of (120/179)

Sharma SP, et al. Heart Rhythm. 2019 Jul;16(7):990‐995 Sharma SP, et al. Heart Rhythm. 2019 Jul;16(7):990‐995 NSR: normal sinus rhythm 7 ICD: implantable cardioverter‐defibrillator 8 Nicolas Tran, Pharm.D. Nicolas Tran, Pharm.D. 78

Purpose Methodology

Study Design •Single‐center, retrospective chart review

Study time frame • January 1st, 2014 to December 31st, 2019 Is it safe to switch to dofetilide within three months of discontinuing amiodarone in Patients •38 patients included patients with atrial fibrillation?

•Evaluate the safety of switching to dofetilide Primary Objective within three months of discontinuing amiodarone in patients with atrial fibrillation

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Institution Overview Patient Population

Tampa General Hospital Inclusion Criteria Exclusion Criteria TN80 •Age ≥ 18 years •Previous dofetilide therapy •Private, not‐for‐profit • Diagnosis of atrial •History of QTc prolongation fibrillation or Torsades de Pointes •Academic medical center •Initiated on dofetilide • clearance < 20 •Level 1 trauma center within 3 months of mL/min discontinuing amiodarone •Concomitant class I or class •Licensed beds: 1,007 • Followed by cardiology or III antiarrhythmic drugs electrophysiology

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TN80 Reasons for exclusion: -Not on amiodarone prior to dofetilide (n=19) -Previous dofetilide therapy (n=19) -Amiodarone stopped > 3 months (n=11) Tran, Nicolas, 4/3/2021 5/13/2021

Study Objectives Baseline Demographics

Primary Outcomes Baseline Characteristics Age, years 62.8 ± 10.1 Creatinine clearance, mL/min 105.8 ± 44.9 •Incidence of QTc prolongation Sex, n (%) Electrolytes Male 26 (68.4%) Serum potassium, mEq/L 4.2 ±0.4 •Incidence of Torsades de Pointes Female 12 (31.6%) Serum , mEq/L 2.1 ±0.2 Race, n (%) QTc, ms 437.7 ± 36.7 Additional Safety Outcomes Caucasian 32 (84.2%) 0 to 7 days 444.7 ± 38.9 Hispanic 3 (7.9%) 8 to 14 days 413.7 ± 30.6 • Discontinuation of dofetilide therapy Other 3 (7.9%) > 14 days 432.0 ± 14.5 Weight, kg 99.0 ± 32.3 QTc prolonging agent, n (%) 18 (47.4%) •Re‐hospitalization within 30 days BMI, kg/m2 31.4 ±7.0 Heart rate, bpm 83.2 ± 23.2 •All‐cause mortality within 180 days ICD present, n (%) 7 (18.4%) Pacemaker present, n (%) 5 (13.2%) Abbreviations: BMI, body mass index; ICD, implantable cardioverter‐defibrillator; bpm, beats per minute

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Primary Safety Outcomes QTc Prolongation Stratified by Subgroup

Incidence of QTc Prolongation Incidence of QTc Prolongation 100% 100.0% p=0.43 90% (3/3) 0 to 7 days 80% 37% p=0.23 8 to 14 days 70% 50% n=38 > 14 days 60% p=1.00 No QTc Prolongation 50% 8% 50.0% 5% 40% 45.2% (2/4) 30% (14/31) 20% Characteristics of Patients with Torsades de Pointes 10% Patient Number of Doses Baseline QTc Interactions Transition ICD 0% 57‐year‐old male 11TN77 408 ms N/A 3.5 days Present 0 to 7 days 8 to 14 days > 14 days 60‐year‐old male 2TN78 442 ms Ondansetron 49 days N/A Time Period Between Amiodarone and Dofetilide Transition Abbreviation: ICD, implantable cardioverter‐defibrillator

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Dofetilide Dosing Secondary Endpoints

Dosing During the Initiation Period Initial dose, n (%) 500 mcg 32 (84.2%) n=38 Dofetilide Therapy Prior to Discharge 250 mcg 6 (15.8%) Dose adjustment, n (%) 15 (39.5%) Second dose, n (%) Reason for dose adjustment, n (%) 500 mcg 31 (83.8%) n=37 QTc prolongation 11 (73.3%) Post‐Discharge Safety Outcomes 250 mcg 6 (16.2%) Bradycardia 2 (13.3%) Re‐hospitalization within 30 days, n (%) 7 (18.4%) Third dose, n (%) Unspecified* 2 (13.3%) TN81Reason for hospitalization, n (%) 500 mcg 26 (70.3%) n=36 Dofetilide discontinuation, n (%) 11 (28.9%) 250 mcg 11 (28.9%) Atrial Fibrillation with RVR 3 (42.9%) Reason for discontinuation, n (%) Acute respiratory distress 1 (14.3%) Fourth dose, n (%) NSVT 3 (27.3%) Bradycardia 1 (14.3%) 500 mcg 26 (72.2%) n=36 Breakthrough atrial tachycardia 2 (18.2%) Endomyocardial biopsy 1 (14.3%) 250 mcg 10 (27.8%) Torsades de Pointes 2 (18.2%) NVST 1 (14.3%) Fifth dose, n (%) QTc prolongation 1 (9.1%) All‐cause mortality within 180 days , n (%) 1 (2.6%) 500 mcg 20 (55.6%) Bradycardia 1 (9.1%) 250 mcg 14 (38.9%) n=35 Heart Transplant 1 (9.1%) Abbreviation: RVR, rapid ventricular rate; NSVT, non‐sustained 125 mcg 1 (2.8%) Deceased 1 (9.1%) ventricular tachycardia Sixth dose, n (%) *Not due to QTc prolongation, bradycardia, or renal dose adjustment 500 mcg 17 (48.6%) Abbreviation: NSVT, non‐sustained ventricular tachycardia 250 mcg 13 (37.1%) n=32 125 mcg 2 (5.7%)

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TN77 Patient received 10 doses of 500 mcg and was dose adjusted to 250 mcg due to QTc prolongation. Torsades de Pointes occurred after 250 mcg dose. Tran, Nicolas, 3/8/2021 TN78 Patient received 2 doses of 500 mcg before experiencing Torsades de Pointes. Tran, Nicolas, 3/8/2021

Slide 18

TN81 Drug discontinuation: DIAMOND: 29% Sharma et al: 6.1% For our study, safety was not the only reason for drug discontinution a total of 3 patients were taken off dofetilide for QTc or TdP prior to discharge (3/38; 7.9%) Tran, Nicolas, 4/9/2021 5/13/2021

Limitations Conclusion

Retrospective design This is the first study to describe the safety of rapidly transitioning • Selection bias and potential confounding to dofetilide within seven days of amiodarone discontinuation • Changes in standards of practice and physician preferences

No comparator group QTc prolongation occurred in half of the patients during the initiation period, and the incidence of TdP was 5.3% •Lack of comparison to washout period of ≥ 3 months •Higher rate of Torsades de Pointes than patients in dofetilide clinical trials •Effect of small sample size? The transition from amiodarone to dofetilide within three months appears to be safe QTc Interpretation Method

•Automated QTc analyses were used unless a manually calculated QTc was available A transition period within seven days may be reasonable, but the • Innate limitations of automated QTc analyses optimal timing of transition remains unknown • Selected due to the consistency of availability

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Self‐Assessment Acknowledgments

True or False. In this study, the timing of the transition • from amiodarone to dofetilide significantly impacted Juline Wilhelm, BS the incidence of QT prolongation at the pre‐specified • Matthew Noble, Pharm.D. subgroups of 0‐7 day, 8‐14 day, and > 14 day transition • Sanders Chae, MD, JD, FACC, FHRS periods.

A. True B. False

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Notable Findings

Mean QTc and Heart Rate at Various Timepoints 470 85 465 80

460 minute)

455 75 per (ms) Safety of Immediate Dofetilide Initiation Post

450 70 Amiodarone Therapy QTc 445 (beats 65 440 Rate Nicolas Tran, Pharm.D. 435 60

PGY‐1 Pharmacy Resident Heart Tampa General Hospital [email protected] QTc Heart Rate

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Impact of Potential Drug Interactions

Duration of Transition Incidence of QTc Prolongation OR [95% CI] QT Prolonging Agent No QT Prolonging Agent Total (n=38) 10/18 (55.6%) 9/20 (45.0%) 1.53 [0.42‐5.50] 0 to 7 days (n=31) 6/13 (46.2%) 8/18 (44.4%) 1.07 [0.26‐4.49] 8 to 14 days (n=3) 2/2 (100.0%) 1/1 (100.0%) 1.67 [0.02‐137.36] > 14 days (n=4) 2/3 (66.7%) 0/1 (0.0%) 5.0 [0.11‐220.64] CYP 3A4 Inhibitor No CYP 3A4 Inhibitor Total (n=38) 7/17 (41.2%) 12/21 (57.1%) 0.53 [0.14‐1.92] 0 to 7 days (n=31) 6/14 (42.9%) 8/17 (47.1%) 0.84 [0.20‐3.50] 8 to 14 days (n=3) 1/1 (100.0%) 2/2 (100.0%) 0.60 [0.01‐49.45] > 14 days (n=4) 0/2 (0.0%) 2/2 (100.0%) 0.04 [0.001‐2.93] Both Neither Total (n=38) 5/10 (50.0%) 14/28 (50.0%) 1.00 [0.24‐4.24] 0 to 7 days (n=31) 4/8 (50.0%) 10/23 (43.5%) 1.30 [0.26‐6.52] 8 to 14 days (n=3) 1/1 (100.0%) 2/2 (100.0%) 0.60 [0.01‐49.45] > 14 days (n=4) 0/1 (0.0%) 2/3 (66.7%) 0.20 [0.005‐8.83]

Concurrent QTc prolonging agents, CYP 3A4 inhibitors, or both did not increase the risk of QTc prolongation even when adjusted for the timing of transitionTN79

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TN79 Most common QTc prolonging agents concurrently ordered during the admission was ondansetron --> antidepressants (, sertraline, paroxetine, and escitalopram) --> antipsychotics (, quetiapine, prochloperazine), antibiotics (levofloxacin and ciprofloxacin), and antifungals ( and voriconazole)

Diltiazem was implicated in all of the CYP3A4 inhibitor interactions. Others included one patient each additionally receiving itraconazole and voriconazole. Tran, Nicolas, 3/8/2021